Kenney M Cristina, Chwa Marilyn, Atilano Shari R, Falatoonzadeh Payam, Ramirez Claudio, Malik Deepika, Tarek Mohamed, Cáceres-del-Carpio Javier, Nesburn Anthony B, Boyer David S, Kuppermann Baruch D, Vawter Marquis, Jazwinski S Michal, Miceli Michael, Wallace Douglas C, Udar Nitin
Gavin Herbert Eye Institute, Department of Pathology and Laboratory Medicine,
Gavin Herbert Eye Institute.
Hum Mol Genet. 2014 Jul 1;23(13):3537-51. doi: 10.1093/hmg/ddu065. Epub 2014 Feb 28.
Age-related macular degeneration (AMD) is the leading cause of vision loss in developed countries. While linked to genetic polymorphisms in the complement pathway, there are many individuals with high risk alleles that do not develop AMD, suggesting that other 'modifiers' may be involved. Mitochondrial (mt) haplogroups, defined by accumulations of specific mtDNA single nucleotide polymorphisms (SNPs) which represent population origins, may be one such modifier. J haplogroup has been associated with high risk for AMD while the H haplogroup is protective. It has been difficult to assign biological consequences for haplogroups so we created human ARPE-19 cybrids (cytoplasmic hybrids), which have identical nuclei but mitochondria of either J or H haplogroups, to investigate their effects upon bioenergetics and molecular pathways. J cybrids have altered bioenergetic profiles compared with H cybrids. Q-PCR analyses show significantly lower expression levels for seven respiratory complex genes encoded by mtDNA. J and H cybrids have significantly altered expression of eight nuclear genes of the alternative complement, inflammation and apoptosis pathways. Sequencing of the entire mtDNA was carried out for all the cybrids to identify haplogroup and non-haplogroup defining SNPs. mtDNA can mediate cellular bioenergetics and expression levels of nuclear genes related to complement, inflammation and apoptosis. Sequencing data suggest that observed effects are not due to rare mtDNA variants but rather the combination of SNPs representing the J versus H haplogroups. These findings represent a paradigm shift in our concepts of mt-nuclear interactions.
年龄相关性黄斑变性（AMD）是发达国家视力丧失的主要原因。虽然与补体途径中的基因多态性有关，但许多携带高风险等位基因的个体并未患AMD，这表明可能涉及其他“修饰因子”。线粒体（mt）单倍群由代表人群起源的特定线粒体DNA单核苷酸多态性（SNP）积累所定义，可能就是这样一种修饰因子。J单倍群与AMD的高风险相关，而H单倍群具有保护作用。很难确定单倍群的生物学后果，因此我们创建了人视网膜色素上皮细胞系-19胞质杂种（胞质杂种），它们具有相同的细胞核，但线粒体分别为J或H单倍群，以研究它们对生物能量学和分子途径的影响。与H胞质杂种相比，J胞质杂种的生物能量学特征发生了改变。定量PCR分析显示，线粒体DNA编码的七个呼吸复合体基因的表达水平显著降低。J和H胞质杂种的替代补体、炎症和凋亡途径的八个核基因的表达发生了显著改变。对所有胞质杂种进行了整个线粒体DNA的测序，以鉴定单倍群和非单倍群定义的SNP。线粒体DNA可以介导细胞生物能量学以及与补体、炎症和凋亡相关的核基因的表达水平。测序数据表明，观察到的心弦并不是由于罕见的线粒体DNA变异，而是代表J与H单倍群的SNP的组合。这些发现代表了我们对线粒体-细胞核相互作用概念的范式转变。
